The Importance of Maintaining Reproductive Choices for Kidney Transplant Recipients

The first successful pregnancy in a kidney transplant recipient occurred in 1958,¹ only 4 years after the first successful kidney transplant. Since then, nearly 2300 pregnancies in kidney transplant recipients have been reported to the Transplant Pregnancy Registry International (TPRI), a worldwide, voluntary registry of pregnancy outcomes in persons with solid organ transplants.² The TPRI likely underestimates the true rate of post-transplant pregnancies given that 15% of kidney transplant recipients in the United States alone are persons of child-bearing age.³ The desire for parenthood in kidney transplant recipients approximates that in the general population, and for many transplant recipients, having children is an essential component of recovering a sense of normalcy after transplantation.⁴ The live birth rate (i.e., the proportion of clinically detectable pregnancies that result in a living child), among kidney transplant recipients reported in the TPRI, is comparable with that in the general US population.²

Despite the many successful pregnancies that have occurred, post-transplant pregnancy can pose significant risks to the gestational parent, the fetus, and the allograft. It is imperative that patients are appropriately counseled on potential pregnancy-associated risks to their allograft and general health so that they can make informed choices. Specifically, rates of preeclampsia are higher in kidney transplant recipients than in the general population.¹ Mycophenolic acid (MPA) products, which are a common component of post-transplant immunosuppressive regimens, are teratogenic and associated with increased rates of first-term miscarriage.² Infants born to kidney transplant recipients are frequently delivered preterm and small for gestational age.² Exposure to fetal antigens and fluctuations in immunosuppressive drug levels can increase the potential for rejection of the allograft.^5,6 Based on a patient's individual circumstance, post-transplant pregnancy may represent an unacceptably high health risk for some including those with decreased allograft function and proteinuria. Pregnancy risks are even greater in patients with an additional nonkidney transplant or multiorgan (i.e., combined kidney pancreas) transplant. Therefore, access to specialized reproductive health resources is essential for the proper care of pregnant transplant recipients and those considering future pregnancy.

Regrettably, some parts of the United States have recently reduced access to the full range of family planning options available, and notably, some of these areas have the worst gestational parent and fetal outcomes observed in the general population. These restrictions threaten outcomes for transplant recipients and preclude health care workers in these areas from providing guideline-based care to their patients and will disproportionally affect transplant recipients from minority racial and ethnic groups and lower socioeconomic groups. In response to the overturning of Roe versus Wade, the American Society of Transplantation issued a statement⁷ stressing the importance of providing access to routine and emergency contraception as well as safe abortion care when required.

Preconception counseling and comprehensive care are essential for patients with kidney disease, including those undergoing transplant workup and at various stages of post-transplant follow-up. In recognition of patient desires for post-transplant pregnancy and to mitigate the associated risks to the extent possible, best practice statements⁸ have made specific recommendations regarding appropriate patient counseling and management. Pregnancy should be avoided for at least 1 year post-transplant or 1 year after treatment for rejection. One registry study⁹ demonstrated additional benefit among those who waited to conceive until at least 2 years post-transplant. All post-transplant pregnancies should be planned and MPA discontinued at least 6 weeks before conception⁸; it is frequently replaced with azathioprine. Patients who have abnormal allograft function (elevated serum creatinine or significant proteinuria) at conception may face even greater risk of pregnancy and transplant complications.¹⁰ Consultation and comanagement with high-risk obstetrics or maternal fetal medicine specialists as part of multidisciplinary teams is recommended. It is essential for transplant recipients to be counseled about and have access to all options to prevent a poorly timed pregnancy.

Despite identification of these risk reduction strategies, as physicians we recognize that there will still be kidney transplant recipients who have medically complicated pregnancies as well as pregnancies that are unplanned. In the TPRI, 30% of all pregnancies among kidney transplant recipients were considered “unplanned” and 8% had exposure to MPA in the first trimester.² Nearly 30% of kidney recipients experience preeclampsia, and approximately half are diagnosed with hypertensive disorders of pregnancy.² While acute rejection rates during pregnancy were low (3%), unfortunately 5.4% of kidney recipients experienced graft loss within 2 years postpartum.² Consistent with trends observed in the general US population,¹¹ pregnancy terminations appear to have declined among kidney transplant recipients¹² and represent only 4% of all pregnancy outcomes reported in the TPRI.² A paucity of research likely leads to gaps in clinical care. In the experience of one of the authors of this viewpoint article as a patient, the risks and benefits, safety, and efficacy of infertility treatments were inadequately discussed. Likewise, physicians may not feel sufficiently informed to discuss alternative routes to parenthood for patients in whom the risk of post-transplant pregnancy is prohibitively high.

There are broader implications to access to reproductive health care beyond routine clinical care. A full range of reproductive health choices, including highly effective contraception, is also necessary for equitable participation in clinical trials. Transplant recipients must demonstrate that they are taking measures to prevent pregnancy and avoid fetal exposure to potentially teratogenic investigational medication to participate in clinical studies. Unequal access to reliable contraception will exacerbate preexisting sex bias and gender imbalance in clinical trials in transplantation and potentially exacerbate disparities in access to novel therapeutics. Depending on the clinical context, maintaining equitable access to reproductive options may include educating patients about fertility preservation, intrauterine insemination or in vitro fertilization as treatments for infertility, and surrogacy as an alternative to a medically complicated pregnancy and is an essential component of comprehensive post-transplant care.

For over 50 years, transplant physicians have supported transplant recipients through successful post-transplant pregnancies. Central to this success has been identifying the right time for pregnancy in the right patient and to provide appropriate therapeutic options when pregnancy is unsafe. As transplant physicians, we are obligated to provide the best care for our patients. We are deeply concerned about the serious risk to patient care in locations where access to reproductive options is now legally restricted or compromised. We urge policy makers to recognize the unique considerations of transplant recipients and believe that failure to provide access to essential and optimal reproductive health care will lead to adverse birth and patient outcomes including allograft loss and death.

Disclosures

D. Sawinski reports Ownership Interest: CareDx; Research Funding: National Institutes of Health; Advisory or Leadership Role: American Journal of Kidney Diseases, Clinical Transplantation, Councilor at Large for American Society of Transplantation Board of Directors; and Other Interests or Relationships: UNOS Kidney Committee member, and Expert witness testimony. S.V. Niederhaus reports Consultancy: Memo Therapeutics; Honoraria: ASN/CDC; and Advisory or Leadership Role: National Kidney Foundation of Maryland/Delaware Board Member. J.S. Gill reports Consultancy: Takeda; Veloxis; Research Funding: Astellas; Honoraria: Hansa, Takeda, Veloxis; and Advisory or Leadership Role: American Society of Transplantation, Canadian Blood Services, and Journal of the American Society of Nephrology Associate Editor. Because J.S. Gill is an Associate Editor of the Journal of the American Society of Nephrology, he was not involved in the peer review process for this manuscript. Another editor oversaw the peer review and decision-making process for this manuscript. All remaining authors have nothing to disclose.

Funding

None.

Author Contributions

J.S. Gill and D. Sawinski conceptualized the study; J.S. Gill was responsible for project administration; A. Cunningham, J.S. Gill, E. Hendren, and D. Sawinski wrote the original draft; and A. Cunningham, J.S. Gill, E. Hendren, S.V. Niederhaus, and D. Sawinski reviewed and edited the manuscript.